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  • Review Article
  • Published:

Is cancer triggered by altered signalling of nicotinic acetylcholine receptors?

Nature Reviews Cancer volume 9, pages 195–205 (2009)Cite this article

Key Points

  • Nicotinic acetylcholine receptors (nAChRs) are ion channels that are expressed in the plasma membrane of all mammalian cells, including cancer cells.

  • nAChRs are central regulators that stimulate the synthesis and release of stimulatory and inhibitory neurotransmitters, which in turn regulate the release of growth, angiogenic and neurogenic factors and stimulate signal transduction in a cell-type-specific manner.

  • Chronic exposure to nicotine or nicotine-derived carcinogenic nitrosamines upregulates cancer-stimulatory nAChRs and desensitizes cancer-inhibitory nAChRs.

  • The homomeric α7nAChR is the major stimulator of cancer development and progression: it induces the synthesis and release of autocrine growth factors in small-cell lung cancer and indirectly stimulates most other types of cancer through the systemic and cellular release of stress neurotransmitters that bind as agonists to β-adrenergic receptors.

  • The heteromeric α4β2nAChR is a major inhibitor of cancer development and progression: it stimulates the release of γ-aminobutyric acid, which blocks the cancer stimulating effects of β-adrenergic receptors by inhibiting cyclic AMP.

  • Marker-guided cancer intervention strategies that target nAChRs and their effectors that aim to restore the balance between stimulatory and inhibitory neurotransmitters need to be developed.

Abstract

Nicotinic acetylcholine receptors (nAChRs) are the central regulators of stimulatory and inhibitory neurotransmitters that control the synthesis and release of growth, angiogenic and neurotrophic factors in cancer cells, the cancer microenvironment and distant organs. Data discussed in this Review suggests that smoking and possibly other environmental and lifestyle factors increase the function of nAChRs that stimulate cancer cells and reduce the function of nAChRs that inhibit cancer cells. This novel paradigm necessitates the development of marker-guided cancer intervention strategies that aim to restore the balance between nAChR-mediated stimulatory and inhibitory neurotransmitters and their downstream effectors.

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Figure 1: Conformational changes of ion channels.
Figure 2: The diverse functions of the homomeric α7 nicotinic acetylcholine receptor (nAChR) and of the heteromeric α4β2nAChRs.
Figure 3: Regulation of small-cell lung cancer (SCLC) cells and their cells of origin.
Figure 4: Regulation of non-small-cell lung cancer (NSCLC) cells and their cells of origin.
Figure 5: Regulation of gastrointestinal adenocarcinomas and small-airway-derived adenocarcinoma.
Figure 6: Regulation of tumour angiogenesis and neurogenesis by nicotinic acetylcholine receptors (nAChRs).

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Authors and Affiliations

  1. Department of Pathobiology, Experimental Oncology Laboratory, College of Veterinary Medicine, University of Tennessee, Knoxville, 37996, Tennessee, USA

    Hildegard M. Schuller

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Glossary

Nicotine-derived nitrosamines

Cancer-causing agents formed from nicotine by nitrosation.

Ion channel

A channel in the plasma membrane through which ions flow from the outside to the interior of the cell.

Desensitization

An nAChR is desensitized by a reversible conformational change in the receptor that is characterized by a significant decrease in responsiveness to an agonist.

Phyto-oestrogens

A naturally occurring compound derived from plants or plant products that acts like oestrogen in the body.

β-Adrenergic receptor

G-protein-coupled receptors in effector tissues, most of which are innervated by adrenergic post-ganglionic fibres of the sympathetic nervous system and are activated by noradrenaline, adrenaline and various adrenergic drugs.

Calpains

Proteolytic enzymes that are regulated by Ca2+.

Chronic obstructive pulmonary disease

(COPD). A chronic inflammation of the lungs.

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Schuller, H. Is cancer triggered by altered signalling of nicotinic acetylcholine receptors?. Nat Rev Cancer 9, 195–205 (2009). https://doi.org/10.1038/nrc2590

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